A Polyoxometalate-Based Pathologically Activated Assay for Efficient Bioorthogonal Catalytic Selective Therapy

Since polyoxometalates (POMs) can undergo reversible multi-electron redox transformations, they have been used to modulate the electronic environment of metal nanoparticles for catalysis. Besides, POMs possess unique electronic structures and acid-responsive self-assembly ability. These properties inspired us to tackle the drawbacks of the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction in biomedical applications, such as low catalytic efficiency and unsatisfactory disease selectivity. Herein, we construct molybdenum (Mo)-based POM nanoclusters doped with Cu (Cu-POM NCs) as a highly efficient bioorthogonal catalyst, which is responsive to pathologicallyacid and H₂S for selective antibiofilm therapy. Leveraging the merits of POMs, the Cu-POM NCs exhibit biofilm-responsive self-assembly behavior, efficient CuAAC-mediated in situ synthesis of antibacterial molecules, and a NIR-II photothermal effect selectively triggered by H₂S in pathogens. The consumption of bacterial H₂S at the pathological site by Cu-POM NCs extremely decreases the number of persisterbacteria, which is conducive to the inhibition of bacterial tolerance and elimination of biofilms. Unlocked at pathological sites and endowed with NIR-II photothermal property, the constructed POM-based bioorthogonal catalytic platform provides new insights into the design of efficient and selective bioorthogonal catalysts for disease therapy.